SABCS: Femara Beneficial Even Years After Tamoxifen Ends

Action Points

Advise patients who ask that these studies imply that Femara has a benefit even if it is begun years after treatment with tamoxifen and that the benefit appears to increase over time.

This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.

Also, the longer a woman takes Femara, the greater the benefit in terms of reducing the risk of local recurrence, Paul Goss, M.D., Ph.D., of Massachusetts General Hospital in Boston said at the San Antonio Breast cancer Symposium.

The first finding came from an analysis of 2,594 women who had been in the placebo arm of the landmark MA.17 trial of Femara and were offered the opportunity to switch to the drug after the study was unblinded in October, 2003.

Dr. Goss was principal investigator of the National Cancer Institute of Canada Clinical Trials Group MA-17 study. It found that Femara reduced the risk of recurrence, compared with placebo, by 47% in women who had previously been treated for five years with tamoxifen.

The study's data monitoring committee stopped the study, arguing it would be unethical to continue women in the placebo arm, given the magnitude of the benefit, Dr. Goss said. All told, 1,655 women in the placebo arm decided to begin taking Femara, he said.

Analysis shows a "fantastic, strong benefit for women who elected to switch to letrozole, despite the fact that they had been off tamoxifen for a prolonged period of time," Dr. Goss said in an interview.

Women who switched had significant differences from the women who stopped treatment, he said. They were younger, had more advanced disease, had a worse performance status, and were more likely to have had adjuvant chemotherapy.

Despite that, they had better results in several key categories:

The hazard ratio for disease-free survival was 0.31 in favor of Femara, with a 95% confidence interval ranging from 0.18 to 0.55.

For distant disease-free survival, the hazard ratio was 0.28 (confidence interval ranging from 0.13 to 0.62).

For overall survival, the hazard ratio was 0.53 (confidence interval ranging from 0.28 to 1.00).

For contralateral cancer, the hazard ratio was 0.23 (confidence interval ranging from 0.07 to 0.77).

On other hand, Dr. Goss said, women who switched had a slightly greater rate of bone fracture, which did not reach statistical significance, and a markedly greater incidence of new osteoporosis, which was significant (p<0.007.)

The risk of recurrence after stopping tamoxifen, Dr. Goss said, "is like a biological metronome that keeps ticking every year and you basically close it down, although not entirely, with this drug."

The analysis shows that "adding letrozole to the treatment of these postmenopausal women is clearly better than keeping them on tamoxifen alone," commented William Gradishar, M.D., of Northwestern University School of Medicine in Chicago.

"The fact that even women who were on placebo at first received a strong benefit when they were put on letrozole adds to the point that adding the aromatase inhibitor is important," he said.

The second finding, presented by James Ingle, M.D., of Johns Hopkins, came from a detailed analysis of the MA.17 data, collected before the unblinding.

The bottom line of the analysis, he said, is that "longer is better" when taking Femara.

For the primary endpoint, which was disease-free survival, the risk of recurrence declined over the study, from a hazard ratio of 0.52 in favor of Femara at 12 months to 0.19 at 48 months, when the study was stopped.

A similar pattern was seen for distant disease-free survival, but not for overall survival, where the hazard ratio, ranging from 0.87 to 0.79, favored Femara but did not change significantly over time, he said.

For patients who were node-positive, all three survival endpoints decreased over time, he said, and the declines were significant. For node-negative women, the decline in disease-free survival was significant, but the trends in the other endpoints were not significant, Dr. Ingle said.

Dr. Gradishar said, "The data appear to show that the sooner you add the aromatase inhibitor the better the patient was going to be."

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine